Process for conversion of estrone compounds to estradiol compounds



Patented Dec. 30, 1952 PROCESS FOR ooNvERsIoN or EsraoNE COMPOUNDS TO 'ESTRADIOL COMPOUNDS John :H. Biel,

side Laboratories,

poration of Wisconsin No Drawing. Application July 31, 1950, Serial No. 176,921

Claims.

This invention relates to a process for preparation of estradiol or estradiol esters from estrone orestrone esters.

Tne therapeutic value of l'l-ketosteroids or 17- hydroxysteroids (sexual hormones) such as estrone and estradiol and the fact that estradiol and its esters are more active than estrone and its esters, are Well known. Estradiol and its esters were heretofore produced by hydrogenation of estrone and its esters under high pressure and in the presence of a catalyst such as Ran'ey nickel, platinum, etc. However, such catalytic, high pressure hydrogenation requires expensive equipment, from one to two days time for completion of the reaction, and careful purification of the solvents to prevent poisoning of the catalyst. The amount of material which may he hydrogenated at one time is limited by the size of the pressure equipment available and the operations are difncult to perform on the large scale required for economical manufacture.

Other processes of hydrogenating estrone to estradiol are known, such as the use of lithium aluminum hydride in ether solution. Such process is, however, extremely hazardous and hence impractical for manufacturing purposes. The lithium aluminum hydride process is, however, not usable to convert an estrone ester to an estradiol ester because of cleavage of the ester linkage during the processing.

It is, therefore, one object of the present invention to prepare estradiol and its esters from estrone and its esters at atmospheric pressure and temperature and using only reagents which do not present any hazards.

Another object of the invention is to provide a process for converting estrone and its esters to estradiol or its esters by the use of simple and readily available equipment.

Another object of the invention is to produce the alpha or natural form of estradiol and its esters by hydrogenation of estrone and its esters.

A further object of the invention is to obtain estradiol or its esters from estrone esters dependent upon the group of estrone esters used.

The present process is concerned with the naturally occurring and more highly active forms of estradiol and its esters, which are now generally termed the alpha forms, and such designation will be understood when estradiol or its esters are. named herein. It will also be understood that the esters of estradiol are most effective as they remain in the human body longer than the estrone, estrone esters orestradiol- Generally, the present process comprises the Milwaukee, Wis., assignor' to Lake- Inc., Milwaukee, Wis., a corsteps of dissolving estrone or its estersin one of a group of solvents or mixtures of such solvents and of dissolving an alkali or alkaline borohydride in the same one of the group or the same mixture of solvents. The'two solutions are then mixed and allowed to stand at room temperature and in atmosphere until evolution of hydrogen ceases. Water is then added to the mixture to precipitate either estradiol or an estradiol ester depending upon whether estrone has been used or on which of the estrone esters has been used. The precipitate is washed and dried as usual, and is packaged and sterilized for pharmaceutical use. The reaction proceeds smoothly at room temperature and at atmospheric pressure and the products are readily isolated with approximately quantitative yields.

The following examples illustrate the present process: I

A. Reduction of estrone to estradiol 0.4 g. of estrone is suspended in 20 cc. of hot methanol and dissolved with one drop of 20% aqueous sodium hydroxide. 0.15 g. of sodium borohydride is dissolved in a similar quantity of methanol. The two solutions are mixed and allowed to stand at room temperature and atmospheric pressure. Hydrogen is evolved during the reaction and such evolution ceases when the reaction is completed. Water in quantity no less than (30.0 cc.) that of the reaction mixture is then added thereto to precipitate the estradiol. The pH of the resulting suspension is adjusted to 8.0 with concentrated hydrochloric acid. The mixture is preferably cooled during addition of the water. The precipitate is filtered out, washed with a mixture of equal parts of methanol and water (aqueous methanol) and dried. The yield obtained is 0.35 g. of estradiol, which is of theoretical. Upon recrystallization of the precipitate from aqueous methanol, 0.35 g. of the product were obtained having a melting point of 172-174? C. When a mixed melting point determination is made with estradiol having a melting point of 1'73174 C., the melting point of 172-174 C. was also obtained.

B. Preparation of estradiol from estrone acetate ml and dried. 0.36 g. of estradiol are obtained having a melting point of 174-l75 C.

C. Reduction of estrone-trimethylacetate to estradiol-trimethylacetate 0.9 g. of estrone-trimethylaoetate and 0.25 of sodium borohydride are separately dissolved in 20 cc. of methanol each. The solutions are mixed and allowed to stand at room temperature and in atmosphere until the evolution of hydrogen ceases. A quantity of water approximately equal to the quantity of the reacted mixture is then added thereto.

aqueous methanol and dried. 0.8 g. of estradioltrimethylacetate is obtained having a melting point of 178-180 C.

D. Preparation of estradioZ-tertiarybutylacetate from estrone-tertiarybutylacetate E. Reduction of estrone-benzoate to estradioZ-3-benzoate 0.9 g. of estrone-benzoate are dissolved in cc. of dioxane (the diether of ethylene glycol) and are mixed with 0.25 g. of sodium borohydride dissolved in 10 cc. of methanol. The mixtur is treated as described above and the product obtained is a mixture of estradiol and estradiol-3- benzoate in approximately equal amounts. Because of utility of the mixed product itself, no separation of the two compounds is required.

The present process applies to 17-ketosteroids and more particularly to estrone and to those esters of estrone having the structural formula where X is an alkyl, and aryl group. More specifically, where X is B. may be hydrogen, alkyl, and aryl groups. When at least two of th R groups are alkyl, and aryl groups, or when at least one of the R groups is a bulky group or causes steric hindrance, the product is predominantly the ester. When X has no steric hindrance properties, as when X is a methyl group, the product is estradiol.

The above processes can also be carried out by the substitution of other solvents, provided the liquids used are solvents for estrone and sodium borohydride and inert to sodium boro- "hydride, such solvents being usually of polar The entire mixture is then cooled 1 and filtered and the precipitate is washed with character. The solvents must be non-acidic as, for example, dioxane, ether, ethanol, methanol and other such organic solvents. Aqueous alkalis may be used as the solvent in converting estrone to estradiol but may not be used for the ester conversions as such esters would be hydrolyzed to estrone. The liquid used for washing need not be identical with the solvent or solvents used. Mixtures of solvents and washing liquids may also be used. In ach instance the reaction proceeds smoothly at room temperature and at atmospheric pressure, and substantially quantitative yields are obtained. The reaction is exothermic and larger quantities should be cooled during the reaction, the cooling range being 20-509 C. In'the above xamples, cooling of the mixture is commenced as soon as the water is added to avoid hydrolyzing of the esters formed.

It will thus be seen that the present process converts a 17-ketosteroid to a l7-hydroxysteroid by readily available equipment at room temperature and atmospheric pressure and with quantitative or nearly quantitative yields. No special precautions are required in processing, although it is desirable to cool the reaction vessel when water is added for precipitating the desired product. The product is obtained in high purity which is readily increased by simple re-crystallization. All of the less easily hydrolyzed esters may be produced thus providing a simple process for making a wide range of useful compounds.

Modifications may be made in carrying out the present invention without departing from the spirit and scope thereof and the invention is to be limited only by the scope of the following claims.

I claim:

1. In a process for converting estrone compounds to estradiol compounds of the structural formula pounds to estradiol compounds of the structural formula in which the R. groups consist of alkyl and aryl radicals, the steps of mixing a solution of the estrone compound with a solution of an alkali metal borohydride, the solvent being inert to the borohydride, and of precipitating the estradiol compound by addition of water to the mixture.

3. The process of reducing estrone trimethylacetate to the estradiol ester comprising dissolving the estrone ester in a liquid inert to and a solvent for sodium borohydride, dissolving sodium borohydride in the solvent, mixing the solutions, holding the mixture at room temperature and atmospheric pressure until evolution of hydrogen ceases, and precipitating the estradiol trimethylacetate by adding water to the quiescent mixture.

4. The process of reducing estrone tertiarybutyl acetate to estradiol tertiarybutyl acetate comprising dissolving the estrone ester in a liquid inert to and a solvent for sodium borohydride, dissolving sodium borohydride in the solvent, mixing the solutions, holding the mixture at room temperature and atmospheric pressure until eve-- lution of hydrogen ceases, and precipitating estradiol tertiaiybutylacetate by adding water to the quiescent mixture.

5. The process of reducing estrone benzoate to estradiol-3-benzo-ate comprising dissolving the estrone ester in a liquid inert to and a solvent for sodium borohydride, dissolving sodium borohydride in the solvent, mixing the solutions, holding the mixture at room temperature and atmospheric pressure until evolution of hydrogen ceases, and precipitating estradiol-B-benzoate by adding water to the quiescent mixture.

JOHN H. BIEL.

REFERENCES CITED The following references are of record in the file of this patent:

Ott et al.: Abst. of 113th Meeting of Am. Chem. 800., April 1948, p. 17K. Chaiken et al.: Jour. Am. Chem. Soc. 71. 122-125 (1949). 

1. IN A PROCESS FOR CONVERTING ESTRONE COMPOUNDS TO ESTRADIOL COMPOUNDS OF THE STRUCTURAL FORMULA 